RESUMO
Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.
Assuntos
Glucagon/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Tri-Iodotironina/efeitos dos fármacos , Animais , Aterosclerose/tratamento farmacológico , Peso Corporal/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Engenharia Química/métodos , Colesterol/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Glucagon/efeitos adversos , Glucagon/química , Glucagon/farmacologia , Hiperglicemia/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Tri-Iodotironina/efeitos adversos , Tri-Iodotironina/química , Tri-Iodotironina/farmacologiaRESUMO
Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.
Assuntos
Surdez , Perda Auditiva Central , Atrofia Óptica Autossômica Dominante , Animais , Humanos , Camundongos , GTP Fosfo-Hidrolases/genética , Perda Auditiva Central/genética , Mutação , Atrofia Óptica Autossômica Dominante/genéticaRESUMO
In rats, hypothyroidism during fetal and neonatal development can disrupt neuronal migration and induce the formation of periventricular heterotopia in the brain. However, it remains uncertain if heterotopia also manifest in mice after developmental hypothyroidism and whether they could be used as a toxicological endpoint to detect TH-mediated effects caused by TH system disrupting chemicals. Here, we performed a mouse study where we induced severe hypothyroidism by exposing pregnant mice (n = 3) to a very high dose of propylthiouracil (PTU) (1500 ppm) in the diet. This, to obtain best chances of detecting heterotopia. We found what appears to be very small heterotopia in 4 out of the 8 PTU-exposed pups. Although the incidence rate could suggest some utility for this endpoint, the small size of the ectopic neuronal clusters at maximum hypothyroidism excludes the utility of heterotopia in mouse toxicity studies aimed to detect TH system disrupting chemicals. On the other hand, parvalbumin expression was manifestly lower in the cortex of hypothyroid mouse offspring demonstrating that offspring TH-deficiency caused an effect on the developing brain. Based on overall results, we conclude that heterotopia formation in mice is not a useful toxicological endpoint for examining TH-mediated developmental neurotoxicity.
Assuntos
Hipotireoidismo , Heterotopia Nodular Periventricular , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Feminino , Humanos , Animais , Ratos , Camundongos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Exposição Materna , Hormônios Tireóideos/metabolismo , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/metabolismo , Propiltiouracila/toxicidadeRESUMO
Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.
Assuntos
Transportadores de Ácidos Monocarboxílicos , Simportadores , Animais , Camundongos , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/genética , Simportadores/metabolismo , Sistemas CRISPR-Cas , Hormônios Tireóideos/metabolismo , Modelos Animais de Doenças , Mamíferos/metabolismoRESUMO
We gathered available RNA-seq and ChIP-seq data in a single database to better characterize the target genes of thyroid hormone receptors in several cell types. This database can serve as a resource to analyze the mode of action of thyroid hormone (T3). Additionally, it is an easy-to-use and convenient tool to obtain information on specific genes regarding T3 regulation or to extract large gene lists of interest according to the users' criteria. Overall, this atlas is a unique compilation of recent sequencing data focusing on T3, its receptors, modes of action, targets and roles, which may benefit researchers within the field. A preliminary analysis indicates extensive variations in the repertoire of target genes where transcription is upregulated by chromatin-bound nuclear receptors. Although it has a major influence, chromatin accessibility is not the only parameter that determines the cellular selectivity of the hormonal response.
Assuntos
Receptores dos Hormônios Tireóideos , Hormônios Tireóideos , Animais , Cromatina/genética , Camundongos , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Tri-Iodotironina/metabolismoRESUMO
Thyroid hormones are important for homeostatic control of energy metabolism and body temperature. Although skeletal muscle is considered a key site for thyroid action, the contribution of thyroid hormone receptor signaling in muscle to whole-body energy metabolism and body temperature has not been resolved. Here, we show that T3-induced increase in energy expenditure requires thyroid hormone receptor alpha 1 (TRα1 ) in skeletal muscle, but that T3-mediated elevation in body temperature is achieved in the absence of muscle-TRα1 . In slow-twitch soleus muscle, loss-of-function of TRα1 (TRαHSACre ) alters the fiber-type composition toward a more oxidative phenotype. The change in fiber-type composition, however, does not influence the running capacity or motivation to run. RNA-sequencing of soleus muscle from WT mice and TRαHSACre mice revealed differentiated transcriptional regulation of genes associated with muscle thermogenesis, such as sarcolipin and UCP3, providing molecular clues pertaining to the mechanistic underpinnings of TRα1 -linked control of whole-body metabolic rate. Together, this work establishes a fundamental role for skeletal muscle in T3-stimulated increase in whole-body energy expenditure.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Fibras Musculares de Contração Rápida/fisiologia , Fibras Musculares de Contração Lenta/fisiologia , Músculo Esquelético/fisiologia , Receptores alfa dos Hormônios Tireóideos/fisiologia , Hormônios Tireóideos/farmacologia , Animais , Masculino , Camundongos , Camundongos Knockout , Fibras Musculares de Contração Rápida/citologia , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Lenta/citologia , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Condicionamento Físico Animal , TranscriptomaRESUMO
Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily that act as ligand-dependent transcription factors. Here we identified the ten-eleven translocation protein 3 (TET3) as a TR interacting protein increasing cell sensitivity to T3. The interaction between TET3 and TRs is independent of TET3 catalytic activity and specifically allows the stabilization of TRs on chromatin. We provide evidence that TET3 is required for TR stability, efficient binding of target genes, and transcriptional activation. Interestingly, the differential ability of different TRα1 mutants to interact with TET3 might explain their differential dominant activity in patients carrying TR germline mutations. So this study evidences a mode of action for TET3 as a nonclassical coregulator of TRs, modulating its stability and access to chromatin, rather than its intrinsic transcriptional activity. This regulatory function might be more general toward nuclear receptors. Indeed, TET3 interacts with different members of the superfamily and also enhances their association to chromatin.
Assuntos
Cromatina/metabolismo , Dioxigenases/metabolismo , Receptores alfa dos Hormônios Tireóideos/metabolismo , Domínio Catalítico , Cromatina/genética , Dioxigenases/genética , Regulação da Expressão Gênica , Células HEK293 , Humanos , Imunoprecipitação , Mutação , Nitrilas/farmacologia , Domínios e Motivos de Interação entre Proteínas , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Tiazóis/farmacologia , Receptores alfa dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/metabolismo , Transcrição Gênica , UbiquitinaçãoRESUMO
ERGO (EndocRine Guideline Optimization) is the acronym of a European Union-funded research and innovation action, that aims to break down the wall between mammalian and non-mammalian vertebrate regulatory testing of endocrine disruptors (EDs), by identifying, developing and aligning thyroid-related biomarkers and endpoints (B/E) for the linkage of effects between vertebrate classes. To achieve this, an adverse outcome pathway (AOP) network covering various modes of thyroid hormone disruption (THD) in multiple vertebrate classes will be developed. The AOP development will be based on existing and new data from in vitro and in vivo experiments with fish, amphibians and mammals, using a battery of different THDs. This will provide the scientifically plausible and evidence-based foundation for the selection of B/E and assays in lower vertebrates, predictive of human health outcomes. These assays will be prioritized for validation at OECD (Organization for Economic Cooperation and Development) level. ERGO will re-think ED testing strategies from in silico methods to in vivo testing and develop, optimize and validate existing in vivo and early life-stage OECD guidelines, as well as new in vitro protocols for THD. This strategy will reduce requirements for animal testing by preventing duplication of testing in mammals and non-mammalian vertebrates and increase the screening capacity to enable more chemicals to be tested for ED properties.
Assuntos
Bioensaio , Disruptores Endócrinos/efeitos adversos , Disruptores Endócrinos/análise , Monitoramento Ambiental , Animais , Bioensaio/métodos , Biomarcadores , Data Warehousing , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/metabolismo , Monitoramento Ambiental/métodos , Avaliação do Impacto na Saúde , Implementação de Plano de Saúde , Humanos , Medição de Risco , Especificidade da Espécie , Fluxo de TrabalhoRESUMO
Thyroid hormone is necessary for normal development of the central nervous system, as shown by the severe mental retardation syndrome affecting hypothyroid patients with low levels of active thyroid hormone. The postnatal defects observed in hypothyroid mouse cerebellum are recapitulated in mice heterozygous for a dominant-negative mutation of Thra, the gene encoding the ubiquitous TRα1 receptor. Using CRE/loxP-mediated conditional expression approach, we found that this mutation primarily alters the differentiation of Purkinje cells and Bergmann glia, two cerebellum-specific cell types. These primary defects indirectly affect cerebellum development in a global manner. Notably, the inward migration and terminal differentiation of granule cell precursors is impaired. Therefore, despite the broad distribution of its receptors, thyroid hormone targets few cell types that exert a predominant role in the network of cellular interactions that govern normal cerebellum maturation.
Assuntos
Cerebelo/embriologia , Neuroglia/metabolismo , Células de Purkinje/metabolismo , Receptores alfa dos Hormônios Tireóideos/metabolismo , Tri-Iodotironina/metabolismo , Animais , Diferenciação Celular/genética , Movimento Celular/genética , Proliferação de Células , Cerebelo/citologia , Cerebelo/metabolismo , Proteínas do Olho/biossíntese , Proteínas de Homeodomínio/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/biossíntese , Proteínas Repressoras/biossíntese , Receptores alfa dos Hormônios Tireóideos/genéticaRESUMO
TRα1 and TRß1, the two main thyroid hormone receptors in mammals, are transcription factors that share similar properties. However, their respective functions are very different. This functional divergence might be explained in two ways: it can reflect different expression patterns or result from different intrinsic properties of the receptors. We tested this second hypothesis by comparing the repertoires of 3,3',5-triiodo-L-thyronine (T3)-responsive genes of two neural cell lines, expressing either TRα1 or TRß1. Using transcriptome analysis, we found that a substantial fraction of the T3 target genes display a marked preference for one of the two receptors. So when placed alone in identical situations, the two receptors have different repertoires of target genes. Chromatin occupancy analysis, performed at a genome-wide scale, revealed that TRα1 and TRß1 cistromes were also different. However, receptor-selective regulation of T3 target genes did not result from receptor-selective chromatin occupancy of their promoter regions. We conclude that modification of TRα1 and TRß1 intrinsic properties contributes in a large part to the divergent evolution of the receptors' function, at least during neurodevelopment.
Assuntos
Genoma , Neurônios/fisiologia , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/fisiologia , Sequência de Aminoácidos , Animais , Cromatina/metabolismo , Camundongos , Dados de Sequência Molecular , Neurônios/metabolismo , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Receptores dos Hormônios Tireóideos/metabolismo , TranscriptomaRESUMO
Neurons in the CNS of higher vertebrates lose their ability to regenerate their axons at a stage of development that coincides with peak circulating thyroid hormone (T(3)) levels. Here, we examined whether this peak in T(3) is involved in the loss of axonal regenerative capacity in Purkinje cells (PCs). This event occurs at the end of the first postnatal week in mice. Using organotypic culture, we found that the loss of axon regenerative capacity was triggered prematurely by early exposure of mouse PCs to T(3), whereas it was delayed in the absence of T(3). Analysis of mutant mice showed that this effect was mainly mediated by the T(3) receptor α1. Using gain- and loss-of-function approaches, we also showed that Krüppel-like factor 9 was a key mediator of this effect of T(3). These results indicate that the sudden physiological increase in T(3) during development is involved in the onset of the loss of axon regenerative capacity in PCs. This loss of regenerative capacity might be part of the general program triggered by T(3) throughout the body, which adapts the animal to its postnatal environment.
Assuntos
Cerebelo/fisiologia , Fatores de Transcrição Kruppel-Like/genética , Regeneração Nervosa/fisiologia , Células de Purkinje/fisiologia , Tri-Iodotironina/metabolismo , Adaptação Fisiológica/fisiologia , Animais , Axônios/fisiologia , Axotomia , Cerebelo/crescimento & desenvolvimento , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , Lentivirus/genética , Masculino , Camundongos , Camundongos Knockout , Regeneração Nervosa/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Gravidez , Células de Purkinje/efeitos dos fármacos , Receptores dos Hormônios Tireóideos/metabolismo , Tri-Iodotironina/farmacologiaRESUMO
BACKGROUND: Thyroid hormone receptors TRα1, TRß1 and TRß2 are broadly expressed and exert a pleiotropic influence on many developmental and homeostatic processes. Extensive genetic studies in mice precisely defined their respective function. SCOPE OF REVIEW: The purpose of the review is to discuss two puzzling issues: MAJOR CONCLUSIONS: Mouse genetics support a balanced contribution of expression pattern and receptor intrinsic properties in defining the receptor respective functions. The molecular mechanisms sustaining cell specific response remain hypothetical and based on studies performed with other nuclear receptors. GENERAL SIGNIFICANCE: The isoform-specificity and cell-specificity questions have many implications for clinical research, drug development, and endocrine disruptor studies. This article is part of a Special Issue entitled Thyroid hormone signalling.
Assuntos
Receptores dos Hormônios Tireóideos/fisiologia , Animais , Humanos , Isoformas de Proteínas , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Transdução de Sinais , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismoRESUMO
Thyroid hormone is required for the timely transition of Sertoli cells from proliferative to differentiating and maturing. This transition takes place during a critical developmental period in mammals, which in mice is the first post-natal week. In order to identify the underlying molecular mechanisms of this differentiation process, we used Cre/loxP technology to selectively block the function of the thyroid hormone receptor TRα1 in Sertoli cells. We then used RNA-seq to analyze the changes in gene expression induced in the post-natal testis. This differential analysis provides genetic clues to the initial testicular defects resulting from disrupted thyroid hormone signaling, and suggests that Sertoli cells influence germ cells soon after their birth.
Assuntos
Regulação da Expressão Gênica/genética , Modelos Animais , Células de Sertoli/metabolismo , Receptores alfa dos Hormônios Tireóideos/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Transgênicos , Mutação/genética , Análise de Sequência de RNA , Receptores alfa dos Hormônios Tireóideos/genética , Fatores de TempoRESUMO
The nuclear receptors of thyroid hormone exert a broad influence on brain development and then on adult brain physiology. However, the cell-autonomous function of the receptors is combined with their indirect influence on cellular interactions. Mouse genetics allows one to distinguish between these 2 modes of action. It revealed that 1 of the main cell-autonomous functions of these receptors is to promote the maturation of GABAergic neurons. This review presents our current understanding of the action of thyroid hormone on this class of neurons, which are the main inhibitory neurons in most brain areas.
Assuntos
Neurônios GABAérgicos , Receptores dos Hormônios Tireóideos , Hormônios Tireóideos , Animais , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Receptores dos Hormônios Tireóideos/metabolismo , Receptores dos Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/fisiologia , Humanos , Camundongos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismoRESUMO
Mice were exposed to a low dose of the model thyroid hormone disruptor, propylthiouracil. Although this had only a modest effect on maternal thyroid hormones production, postnatal analysis of the pups' plasma by mass spectrometry and the brain striatum by RNA sequencing gave evidence of low lasting changes that could reflect an adverse effect on neurodevelopment. Overall, these methods proved to be sensitive enough to detect minor disruptions of thyroid hormone signalling in vivo.
Assuntos
Hormônios Tireóideos , Transcriptoma , Animais , Camundongos , Glândula Tireoide , Propiltiouracila/farmacologia , EncéfaloRESUMO
Gestating mice were exposed to three chemicals, tetrabromo-bisphenol A (TBBPA; 2mg/kg/day)), amitrole (25 and 50mg/kg/day) and pyraclostrobin (0.4 and 2mg/kg/day) to assess their capacity to act as thyroid hormone disruptors and compromise neurodevelopment. Propyl-thio-uracyl, a known pharmacological inhibitor of thyroid gland secretion, was used at both high and low dose as a reference thyroid hormone disruptor (1 ppm, 1500 ppm). A combination of plasma metabolomics and striatum transcriptomics revealed the induced change in pups at the postnatal stages. Although the underlying mechanism is unlikely to involve thyroid hormone disruption, these chemicals had a detectable effect on pups' neurodevelopment.
RESUMO
Thyroid hormones are known to trigger metamorphosis in an amphibian. This review discusses the hypothesis according to which they act in a similar manner to synchronize the post-natal development of mice, using brain, brown adipose tissue, and heart as examples.
Assuntos
Receptores dos Hormônios Tireóideos , Hormônios Tireóideos , Animais , Camundongos , Metamorfose Biológica , AnfíbiosRESUMO
Thyroid hormone (TH) signaling plays a major role in mammalian brain development. Data obtained in the past years in animal models have pinpointed GABAergic neurons as a major target of TH signaling during development, which opens up new perspectives to further investigate the mechanisms by which TH affects brain development. The aim of the present review is to gather the available information about the involvement of TH in the maturation of GABAergic neurons. After giving an overview of the kinds of neurological disorders that may arise from disruption of TH signaling during brain development in humans, we will take a historical perspective to show how rodent models of hypothyroidism have gradually pointed to GABAergic neurons as a main target of TH signaling during brain development. The third part of this review underscores the challenges that are encountered when conducting gene expression studies to investigate the molecular mechanisms that are at play downstream of TH receptors during brain development. Unravelling the mechanisms of action of TH in the developing brain should help make progress in the prevention and treatment of several neurological disorders, including autism and epilepsy.
Assuntos
Hipotireoidismo , Doenças do Sistema Nervoso , Animais , Humanos , Hormônios Tireóideos/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Hipotireoidismo/genética , Roedores/metabolismo , Mamíferos/metabolismo , Neurônios GABAérgicos/metabolismoRESUMO
Thyroid hormone increases energy expenditure. Its action is mediated by TR, nuclear receptors present in peripheral tissues and in the central nervous system, particularly in hypothalamic neurons. Here, we address the importance of thyroid hormone signaling in neurons, in general for the regulation of energy expenditure. We generated mice devoid of functional TR in neurons using the Cre/LoxP system. In hypothalamus, which is the center for metabolic regulation, mutations were present in 20% to 42% of the neurons. Phenotyping was performed under physiological conditions that trigger adaptive thermogenesis: cold and high-fat diet (HFD) feeding. Mutant mice displayed impaired thermogenic potential in brown and inguinal white adipose tissues and were more prone to diet-induced obesity. They showed a decreased energy expenditure on chow diet and gained more weight on HFD. This higher sensitivity to obesity disappeared at thermoneutrality. Concomitantly, the AMPK pathway was activated in the ventromedial hypothalamus of the mutants as compared with the controls. In agreement, sympathetic nervous system (SNS) output, visualized by tyrosine hydroxylase expression, was lower in the brown adipose tissue of the mutants. In contrast, absence of TR signaling in the mutants did not affect their ability to respond to cold exposure. This study provides the first genetic evidence that thyroid hormone signaling exerts a significant influence in neurons to stimulate energy expenditure in some physiological context of adaptive thermogenesis. TR function in neurons to limit weight gain in response to HFD and this effect is associated with a potentiation of SNS output.
Assuntos
Obesidade , Hormônios Tireóideos , Masculino , Camundongos , Animais , Obesidade/genética , Obesidade/metabolismo , Hormônios Tireóideos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Tecido Adiposo Marrom/metabolismo , Neurônios/metabolismo , Termogênese/fisiologia , Metabolismo Energético/genéticaRESUMO
Thyroid hormone deficiency is known to deeply affect cerebellum post-natal development. We present here a detailed analysis of the phenotype of a recently generated mouse model, expressing a dominant-negative TRα1 mutation. Although hormonal level is not affected, the cerebellum of these mice displays profound alterations in neuronal and glial differentiation, which are reminiscent of congenital hypothyroidism, indicating a predominant function of this receptor isoform in normal cerebellum development. Some of the observed effects might result from the cell autonomous action of the mutation, while others are more likely to result from a reduction in neurotrophic factor production.